Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy

Rita Citraro, Emilio Russo, Francesca Scicchitano, Clementina M van Rijn, Donato Cosco, Carmen Avagliano, Roberto Russo, Giuseppe D'Agostino, Stefania Petrosino, Francesca Guida, Luisa Gatta, Gilles van Luijtelaar, Sabatino Maione, Vincenzo Di Marzo, Antonio Calignano, Giovambattista De Sarro

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85 Citations (Scopus)


N-palmitoylethanolamine (PEA), an endogenous fatty acid ethanolamide, plays a key role in the regulation of the inflammatory response and pain through, among others, activation of nuclear peroxisome proliferator-activated receptors (PPAR-α). Endogenous cannabinoids play a protective role in several central nervous system (CNS) disorders, particularly those associated with neuronal hyperexcitability. We investigated the effects of PEA and the role of PPAR-α in absence epilepsy using the WAG/Rij rat model. PEA, anandamide (AEA), a PPAR-α antagonist (GW6471) and a synthetic CB1 receptor antagonist/inverse agonist (SR141716) were administered to WAG/Rij rats in order to evaluate the effects on epileptic spike-wave discharges (SWDs) on EEG recordings. We studied also the effects of PEA co-administration with SR141716 and GW6471 and compared these effects with those of AEA to evaluate PEA mechanism of action and focusing on CB1 receptors and PPAR-α. Both PEA and AEA administration significantly decreased SWDs parameters (absence seizures). In contrast, GW6471 was devoid of effects while SR141716 had pro-absence effects. The co-administration of SR141716 with PEA or AEA completely blocked the anti-absence effects of these compounds. GW6471 antagonized PEA's effects whereas it did not modify AEA's effects. Furthermore, we have also measured PEA, AEA and 2-AG (2-arachidonoylglycerol) brain levels identifying significant differences between epileptic and control rats such as decreased PEA levels in both thalamus and cortex that might contribute to absence epilepsy. Our data demonstrate that PEA has anti-absence properties in the WAG/Rij rat model and that such properties depend on PPAR-α and indirect activation of CB1 receptors. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.
Original languageEnglish
Pages (from-to)115-126
Number of pages12
Publication statusPublished - Jun 2013

Bibliographical note

Copyright © 2012 Elsevier Ltd. All rights reserved.


  • animals
  • anticonvulsants
  • arachidonic acids
  • calcium channel blockers
  • cannabinoid receptor antagonists
  • dose-response relationship, drug
  • electroencephalography
  • endocannabinoids
  • epilepsy, absence
  • ethanolamines
  • glycerides
  • injections, intraventricular
  • lipid metabolism
  • male
  • oxazoles
  • PPAR alpha
  • palmitic acids
  • piperidines
  • polyunsaturated alkamides
  • pyrazoles
  • rats
  • rats, wistar
  • receptor, cannabinoid, CB1
  • tyrosine


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